Molecular mechanisms of fibrinolysis and their application to fibrin‐specific thrombolytic therapy

AbstractThe fibrinolytic system comprises a proenzyme, plasminogen, which can be converted to the active enzyme, plasmin, which degrades fibrin. Plasminogen activation is mediated by plasminogen activators, which are classified as either tissue‐type plasminogen activators (t‐PA) or urokinase‐type plasminogen activators (u‐PA). Inhibition of the fibrinolytic system may occur at the level of the activators or at the level of generated plasmin.Plasmin has a low substrate specificity, and when circulating freely in the blood it degrades several proteins including fibrinogen, factor V, and factor VIII. Plasma does, however, contain a fast‐acting plasmin inhibitor, α2‐antiplasmin, which inhibits free plasmin extremely rapidly but which reacts much slower with plasmin bound to fibrin. A “systemic fibrinolytic state” may, however, occur by extensive activation of plasminogen and depletion of α2‐antiplasmin. Clot‐specific thrombolysis therefore requires plasminogen activation restricted to the vicinity of the fibrin.Two physiological plasminogen activators, t‐PA and single‐chain u‐PA (scu‐PA) induce clot‐specific thrombolysis, via entirely different mechanisms, however. t‐PA is relatively i